2. Academic Validation
  3. STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma

STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma

  • Cell Rep Med. 2024 Mar 19;5(3):101472. doi: 10.1016/j.xcrm.2024.101472.
Nicole Prutsch 1,  Shuning He 1,  Alla Berezovskaya 1,  Adam D Durbin 2,  Neekesh V Dharia 3,  Kelsey A Maher 4,  Jamie D Matthews 5,  Lucy Hare 6,  Suzanne D Turner 7,  Kimberly Stegmaier 3,  Lukas Kenner 8,  Olaf Merkel 8,  A Thomas Look 9,  Brian J Abraham 10,  Mark W Zimmerman 11
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
  • 2 Division of Molecular Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02141, USA.
  • 4 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5 Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
  • 6 Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Department of Pediatric Oncology and Hematology, Addenbrooke's Hospital, Cambridge, UK.
  • 7 Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 8 Department of Pathology, Unit of Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria.
  • 9 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: thomas_look@dfci.harvard.edu.
  • 10 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: brian.abraham@stjude.org.
  • 11 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: mwz2002@gmail.com.
PMID: 38508140 DOI: 10.1016/j.xcrm.2024.101472
Abstract

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

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